P1393: BISPECIFIC CD19/CD37 CAR-T CELLS IN PATIENTS WITH REFRACTORY OR RELAPSED B-CELL LYMPHOMA
Authors: Wenjing Luo, Chenggong LI, Yinqiang Zhang, Xindi Wang, Zhuolin Wu, Haiming Kou, Cong Lu, Danying Liao, Zejian Chen, Caiqin Chen, Lijun Wu, Wei Xiong, Jun Deng, Yu Hu, Heng Mei
Journal: HemaSphere (2023)

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Anti-CD19 chimeric antigen receptor (CAR) T-cell treatment has showed about 60-80% of response rate in relapsed or refractory (R/R) B-cell lymphoma. However, approximately 40% of patients (PTs) achieved long-term remissions and CD19 antigen target downregulation or loss has been proposed as a common mechanism. CD37, widely expressed on B cells, is involved in lymphoma pathogenesis and immune regulation. Therefore, we generated a bispecific CAR-T cell targeting CD19 and CD37. Preclinical studies found that bispecific CD19/CD37 CAR-T cells were effective against B-cell lymphoma (Cancers 2021,13, 981). Aims: An open-label single arm clinical trial (ChiCTR2100049827) was designed to explore the safety and efficacy of CAR19/37 T-cell therapy for PTs with R/R aggressive B-cell lymphoma. Methods: In this trial, bispecific CAR19/37 was comprised of a murine anti-CD19 scFv (clone FMC63) and humanized anti-CD37 scFv (based on clone 2B8D12F2D4) in loop, and a 4-1BB costimulatory molecule (Figure A). Enrolled PTs had measurable disease with CD19, CD37 or CD19/CD37 expression (Figure B) and have received ≥2 prior lines of therapy. All PTs received cyclophosphamide (500 mg/m2, d-5 to d-4) and fludarabine (30 mg/m2, d-5 to d-3) daily, followed by CAR-T cell infusion at a dose of 0.5x106, 1×106, or 2×106 cells/kg on day 0. The primary endpoint was to characterize the safety. Adverse effects (AEs) were graded using CTCAE v5.0, except that cytokine release syndrome (CRS) and neurotoxicity were graded by ASCTC criteria. Secondary endpoints were pharmacokinetics and efficacy. Lugano criteria (2014) were used for response assessment. Results: As of Feb 22, 2023, 10 PTs s received CD19/CD37 CAR-T cells with a median age of 53 (range 42-67) years old and a median of 3 (range 2-6) prior lines of therapy. Of 10 PTs, 1 was Burkitt lymphoma, 1 was chronic lymphocytic leukemia (CLL) with Ritcher’s transformation, 2 were follicular lymphoma, and the rest were diffuse large B-cell lymphoma. Besides, 6 out of PTs had high-risk cytogenetic profiles, and 2PTs were relapsed after previous CD19 CAR-T cell therapy. Most frequent AEs of grade 3-4 were neutropenia (100%), leukopenia (90%), and thrombocytopenia (30%). 4 PTs (40%) experienced CRS, of which grade 3 CRS occurred once and lasted for 8 days. No neurotoxicity was observed. With follow-up, the overall response was 70%, including 3 complete response (CR) and 4 partial response, and 3 PTs were in ongoing CR (Figure C). PT3 with double-hit lymphoma mainly in tonsil and abdominal cavity did not respond to CAR-T cell therapy and died at month 2. PT8 with two major lesions in abdominal cavity and bilateral neck relapsed from autologous stem cell therapy and further received 3 prior lines of therapy; the patient withdrew from the study at 4 month and survived up to now. PT9 who was CLL with Rither’s transformation relapsed from 6 prior lines of therapy, and the disease progressed on day 12. CAR-T cells peaked at 36766 copies/μg DNA in peripheral blood (PB) (n=9) by droplet digital PCR on day 14 after infusion and were detectable up to 7 months. CAR-T cells peaked at 71830 cells/mL in PB by flow cytometry (FCM) on day 10 after infusion (Figure D). FCM analysis showed that MDSCs and G-MDSCs population were decreased 2 months after CAR-T cells infusion (Figure E). Additionally, PTs with lower TIM-3 expression were inclined to achieve OR (Figure F). Conclusion: In our study, CD19/CD37 CAR-T cells present a good safety and efficacy profile and show immune regulation in R/R aggressive B-cell lymphoma.Keywords: CAR-T, B cell lymphoma, Bispecific